Quinones are a group of aromatic dioxo compounds derived from benzene or multiple-ring hydrocarbons such as naphthalene, anthracene, etc. They are classified as benzoquinones, naphthoquinones, anthraquinones, etc., on the basis of the ring system. Quinones are found in all major groups of organisms as a large and varied group of natural products. Quinones have a variety of medicinal and industrial uses.
Many antineoplastic drugs are either quinones (anthracycline derivatives, mitoxantrone, actinomycin), quinonoid derivatives (quinolones, genistein, bactracyclin), or drugs such as etoposide that can easily be converted to quinones by in vivo oxidation (Gantchev et al. (1997) Biochem. Biophys. Res. Comm. 237:24-27). Quinones are now widely used as anti-cancer, anti-bacterial and anti-malarial drugs, as well as fungicides. The antitumor activities of the quinones were revealed more than two decades ago when the National Cancer Institute published a report in which fifteen-hundred synthetic and natural quinones were screened for their anticancer activities (Driscoll et al. (1974) Cancer Chemot. Reports 4:1-362).
For example, β-lapachone (3,4-dihydro-2,2-dimethyl-2H-naphtho[1,2-b]pyran-5,6-dione) is a quinone derived from lapachol (a naphthoquinone). Lapachol can be isolated from the lapacho tree (Tabebuia avellanedae), a member of the catalpa family (Bignoniaceae). Lapachol and β-lapachone (with numbering) have the following chemical structures:

β-lapachone, as well as its intermediates, derivatives and analogs thereof, are described in Li, C. J. et al., (1993) J. Biol. Chem., 268(30): 22463-22468. As a single agent, β-lapachone has demonstrated significant antineoplastic activity against human cancer cell lines at concentrations typically in the range of 1-10 μM (IC50). Cytotoxicity has been demonstrated in transformed cell lines derived from patients with promyelocytic leukemia (Planchon et al., (1996) Cancer Res., 55: 3706-3711), prostate (Li, C. J., et al., (1995) Cancer Res., 55: 3712-3715), malignant glioma (Weller, M. et al., (1997) Int. J. Cancer, 73: 707-714), hepatoma (Lai, C. C., et al., (1998) Histol Histopathol, 13: 89-97), colon (Huang, L., et al., (1999) Mol Med, 5: 711-720), breast (Wuertzberger, S. M., et al., (1998) Cancer Res., 58: 1876), ovarian (Li, C. J. et al., (1999) Proc. Natl. Acad. Sci. USA, 96(23): 13369-13374), pancreatic (Li, Y., et al., (2000) Mol Med, 6: 1008-1015; Li, Y., (1999) Mol Med, 5: 232-239), and multiple myeloma cell lines, including drug-resistant lines (Li, Y., (2000) Mol Med, 6: 1008-1015). No cytotoxic effects were observed on normal or proliferating human PBMC (Li, Y., (2000) Mol Med, 6: 1008-1015).
β-lapachone appears to work by activating DNA damage response/checkpoint pathways, which may involve unscheduled expression of checkpoint molecules, e.g. E2F1, independent of DNA damage and cell cycle stages. Several studies have shown that β-lapachone activates checkpoint pathways and induces cell death in cancer cells from a variety of tissues without causing death of normal cells from these tissues (U.S. Patent Application Publication No. 2002/0169135, incorporated by reference herein). In normal cells with their intact regulatory mechanisms, such an imposed expression of a checkpoint molecule results in a transient expression pattern and causes little consequence. In contrast, cancer and pre-cancer cells have defective mechanisms. Drug-induced elevation of checkpoint molecules, e.g. E2F1, can lead to selective cell death in these disregulated cells.
In addition to β-lapachone, a number of β-lapachone analogs having antiproliferative properties have been disclosed in the art, such as those described in PCT International Application PCT/US93/07878 (WO94/04145), which is incorporated by reference herein, and U.S. Pat. No. 6,245,807, incorporated by reference herein, in which a variety of substituents may be attached at positions 3- and 4- on the β-lapachone compound. PCT International Application PCT/US00/10169 (WO 00/61142), incorporated by reference herein, discloses β-lapachone, which may have a variety of substituents at the 3-position as well as in place of the methyl groups attached at the 2-position. U.S. Pat. Nos. 5,763,625, 5,824,700, and 5,969,163, each of which is incorporated by reference herein, disclose analogs and derivatives with a variety of substituents at the 2-, 3- and 4-positions. Furthermore, a number of journals report β-lapachone analogs and derivatives with substituents at one or more of the following positions: 2-, 3-, 8- and/or 9-positions, (See, Sabba et al., (1984) J Med Chem 27:990-994 (substituents at the 2-, 8- and 9-positions); (Portela and Stoppani, (1996) Biochem Pharm 51:275-283 (substituents at the 2- and 9-positions); Goncalves et al., (1998) Molecular and Biochemical Parasitology 1: 167-176 (substituents at the 2- and 3-positions)).
U.S. Patent Application Publication No. 2004/0266857 and PCT International Application PCT/US2003/037219 (WO 04/045557), incorporated by reference herein, disclose and several journal reports describe structures having sulfur-containing hetero-rings in the “α” and “β” positions of lapachone (Kurokawa S, (1970) Bulletin of The Chemical Society of Japan 43:1454-1459; Tapia, R A et al., (2000) Heterocycles 53(3):585-598; Tapia, R A et al., (1997) Tetrahedron Letters 38(1):153-154; Chuang, C P et al., (1996) Heterocycles 40(10):2215-2221; Suginome H et al., (1993) Journal of the Chemical Society, Chemical Communications 9:807-809; Tonholo J et al., (1988) Journal of the Brazilian Chemical Society 9(2): 163-169; and Krapcho A P et al., (1990) Journal of Medicinal Chemistry 33(9):2651-2655).
Moreover, PCT Application PCT/US06/20780, incorporated by reference herein, discloses tricyclic spiro-oxathiine naphthoquinone derivatives, a synthetic method for making the derivatives, and the use of the derivatives to induce cell death and/or to inhibit proliferation of cancer or precancerous cells. The naphthoquinone derivatives of the present invention are related to β-lapachone. WO 2006/128120, incorporated by reference herein, discloses sulfur analogs and derivatives of β-lapachone as well as methods of use thereof. These compounds can be used in pharmaceutical compositions for the treatment or prevention of cell proliferation disorders.
In addition to their antineoplastic uses, quinones also have a number of other medicinal uses. Terpenioid-type quinones are also useful as treatments for diabetes. U.S. Pat. No. 5,674,900. Additional quinones can be used to treat cirrhosis and other liver disorders. U.S. Pat. Nos. 5,210,239 and 5,385,942.
Hydroquinone amines and quinone amines are also useful for treating a number of conditions, including spinal trauma and head injury. U.S. Pat. No. 5,120,843. Degenerative central nervous system diseases, as well as vascular diseases, are treatable with quinones such as Idebenone [2,3-dimethoxy-5-methyl-6-(10-hydroxydecyl)-1,4-benzoquinone] and Rifamycin (S. Mordente et al. (1998) Chem. Res. Toxicol. 11:54-63; Rao et al. (1997) Free Radic. Biol. Med 22:439-46; Cortelli et al. (1997)J. Neurol. Sci. 148:25-31; and Mahadik et al. (1996) Prostaglandins Leukot. Essent. Fatty Acids 55:45-54). A vitamin K analog, 6-cyclo-octylamino-5,8-quinoline quinone, shows efficacy for treatment of leprosy and tuberculosis. (U.S. Pat. No. 4,963,565). Hydroquinone is also used to treat skin pigmentation disorders. Clarys et al. (1998) J. Dermatol. 25:412-4. Mitomycin C-related drug indoloquinone EO9 has demonstrated cell killing against HL-60 human leukemia cells, H661 human lung cancer cells, rat Walker tumor cells and human HT29 colon carcinoma cells (Begleiter el al. (1997) Oncol. Res. 9:371-82; and Bailey et al. (1997) Br. J. Cancer 76:1596-603).
Quinones such as aloin, a C-glycoside derivative of anthraquinone, accelerate ethanol oxidation and may be useful in treating acute alcohol intoxication. (Chung et al. (1996) Biochem. Pharmacol. 52:1461-8 and Nanji et al. (1996) Toxicol. Appl. Pharmacol. 140:101-7). Quinones capsaicin and resiniferatoxin blocked activation of nuclear transcription factor NF-κB, which is required for viral replication, immune regulation and induction of various inflammatory and growth-regulatory genes (Singh et al. (1996) J. Immunol. 157:4412-20). Antiretroviral and antiprotozoan naphthoquinones are described in U.S. Pat. Nos. 5,780,514 and 5,783,598. Anthraquinones are also useful as laxatives (Ashraf et al. (1994) Aliment. Pharmacol. Ther. 8:329-36; and Muller-Lissner (1993) Pharmacol. 47 (Suppl. 1): 138-45).
Because of the wide variety of biological processes in which quinones play a critical role, it would be advantageous to develop novel quinones for various uses, including disease treatment.
One obstacle, however, to the development of pharmaceutical formulations comprising quinones, such as β-lapachone or β-lapachone analogs, for pharmaceutical use is the low solubility of many quinone compounds, including β-lapachone compounds, in pharmaceutically acceptable solvents. There are also drawbacks related to the pharmacokinetic profiles of traditional formulations comprising quinones.
U.S. Pat. Nos. 6,962,944 and 7,074,824 disclose pharmaceutical compositions comprising a therapeutically effective amount of β-lapachone, or a derivative or analog thereof, and a pharmaceutically acceptable solubilizing carrier molecule, which may be a water-solubilizing carrier molecule such as hydroxypropyl-β-cyclodextrin, or an oil-based solubilizing carrier molecule, for enhancing the solubility of β-lapachone in aqueous solution. The therapeutically effective amount of β-lapachone, or a derivative or analog thereof, may be complexed with the pharmaceutically acceptable solubilizing carrier molecule in aqueous solution.
WO 2006/020719 discloses quinone prodrug compositions and therapeutic methods using such prodrug compositions. The quinone compounds of the invention are preferably naphthoquinone compounds such as β-lapachone or β-lapachone analogs. The quinone prodrug compositions exhibit improved solubility, stability, bioavailability, and pharmacokinetic properties, as well as improved plasma half-life in vivo.
There is still a need for improved formulations of quinone compounds for pharmaceutical administration, which are both safe and readily bioavailable to the subject to which the formulation is administered.
The references cited herein are not admitted to be prior art to the claimed invention.